PROJECT SUMMARY Type 1 diabetes (T1D) is a genetically controlled disease. While many disease-related genes have been identified in mice and humans, the mechanisms of how these genes produce T1D lags behind their identification. CD137, a T cell co-stimulatory molecule, is the protein product of Tnfrsf9, the prime Idd9.3 (Insulin dependent diabetes) T1D candidate gene. Nonobese diabetic (NOD) mice congenic for the B10 Idd9.3 haplotype (NOD.Idd9.3) are less susceptible to T1D; NOD CD137 is hypofunctional compared to B10 CD137. Our laboratories have published a series of papers on the immunological role of CD137 in T1D. On the one hand, we showed that CD137 deficient NOD mice have decreased T1D incidence, and that splenic T cells lacking CD137 are less diabetogenic. On the other hand, we found that CD137 is constitutively expressed on a subset of Tregs, and that NOD.Idd9.3 mice have increased accumulation of these CD137+ Tregs. CD137+ Tregs are more suppressive than the CD137- subset, partly due to their ability to produce an alternatively spliced CD137 variant, soluble CD137 (sCD137). NOD mice have decreased serum levels of sCD137 compared to NOD.Idd9.3 mice. We made recombinant sCD137 and showed that it prevented T1D in NOD mice. More importantly in a therapeutic context, we show here that recombinant sCD137 can halt acute T1D. We demonstrate that sCD137 directly suppresses CD4 and CD8 T cells in a CD137 Ligand (CD137L) dependent fashion. CD137L mediates ?reverse? signaling, i.e., it not only functions to activate CD137+ cells, but also signals into the CD137L expressing cell. Therefore both CD137 and CD137L actively mediate cell signaling. Active signaling by both receptor and ligand raises critical questions about the mechanism of CD137 in T1D. Hypofunctional NOD CD137 may reduce T effector action, but conversely decrease Treg function and production of immunosuppressive sCD137, thereby reducing CD137L dependent immune regulations. Thus understanding CD137 function in T1D requires defining effects in both CD137+ cells (primarily T and Treg cells) and CD137L+ cells (including APCs and T cells). In this application, we will combine the expertise of our labs to address these issues in the following specific aims. (1) Mechanisms of profound protection from T1D due to CD137 deficiency in CD8 T cells, and functional roles of CD137L expression in immunopathogenesis of T1D. (2) Mechanisms of sCD137-mediated cellular suppression and reversal of NOD new onset T1D. (3) Immunosuppressive function of human sCD137 in human immunity and T1D.